Incidence et causes des blessures par piqûre d'aiguille aux niveaux mondial, régional et national:revue systématique et méta-analyse

Background: Needlestick injuries (NSIs) are one of the most serious occupational hazards for healthcare workers (HCWs). Aims: The aim of this study was to evaluate the incidence and causes of NSIs globally. Methods: A systematic review and meta-analysis of data from January 2000 to May 2020 collected from Scopus, PubMed, Embase, Web of Science, and Google Scholar. The Newcastle–Ottawa Scale was used to assess the quality of the included articles. The data obtained were analysed by R version 3/5/0, and 113 articles were retrieved. Results: There were 113 studies with a total of 525 798 HCWs. The incidence of NSIs was 43%. Africa had the highest rate of these injuries of 51%, and the World Health Organization (WHO) African Region had the highest incidence among WHO regions of 52%. Women were more frequently affected by NSIs than men. Hepatitis C virus infection was the disease most commonly transmitted via NSIs (21%). The highest rates of NSIs according to causes, devices, hospital locations, occupa-tions and procedures were for recapping of needles, needles, general wards, nurses and waste disposal, respectively. Conclusion: The incidence of NSIs is gradually decreasing. The findings of this study can contribute to improving the decision-making process for reducing NSIs in HCWs

The role of ABL/BCR in the leukemogenic potential of BCR/ABL in Philadelphia chromosome positive leukemia

Bei ca. 95% der chronisch myeloischen Leukämie (CML) und 20-30% der akuten lymphatischen Leukämie (ALL) des Erwachsenen liegt eine reziproke Chromosomentranslokation t(9;22)(q34;q11) vor, in deren Rahmen das BCR (Breakpoint Cluster Region) Gen auf Chromosom 22 mit dem ABL (Abelson-Leukämie-Virus) Gen auf Chromosom 9 fusioniert. Auf Chromosom 22 gibt es zwei verschiedene Bruchpunkte, die somit zur Bildung von unterschiedlichen Fusionsgenen führen. Bei der CML findet man den sogenannten „großen“ Bruchpunkt (M-bcr), während bei der Ph+ ALL der sogenannte „kleine“ Bruchpunkt (m-bcr) vorkommt. Das hybride Fusionsgen auf Chromosom 22q+ (Philadelphia-Chromosom) kodiert für das jeweilige BCR/ABL Protein, während das Fusionsgen auf Chromosom 9q+ für das reziproke ABL/BCR Protein kodiert. Das ABL-Protein ist eine Nicht-Rezeptor Tyrosinkinase, die eine wichtige Rolle in der Signaltransduktion und der Regulation des Zellwachstums spielt. Im BCR/ABL Fusionsprotein wird die Kinase-Aktivität von ABL, die im Normalfall streng reguliert ist, durch die Fusion mit BCR konstitutiv aktiv. Dadurch kommt es zur Deregulierung intrazellulärer Signalwege, welche die maligne Transformation hämatopoetischer Zellen verursacht. Eine zielgerichtete Inhibierung von BCR/ABL mittels ABL-Kinase-Inhibitoren induziert Apoptose in BCR/ABL transformierten Zellen, was eine komplette Remission im größten Teil Ph+ Leukämie Patienten zur Folge hat

The functional interplay between the t(9;22)-associated fusion proteins BCR/ABL and ABL/BCR in Philadelphia chromosome positive Acute Lymphatic Leukemia

The successful targeting of BCR/ABL by selective ABL-kinase inhibitors (AKI) such as Imatinib, Nilotinib, or Dasatinib alone is unable to eradicate the leukemic clone in Philadelphia chromosome positive (Ph+ ) leukemia. The t(9;22)(q34;q11) is a balanced translocation. Der22 involves the BCR (breakpoint cluster region) gene locus with two principal breaks: the M-bcr, encoding for the p210BCR/ABL and the m-bcr, encoding for the 185BCR/ABL fusion proteins, respectively. The constitutively activated BCR/ABL kinase is responsible for the leukemic transformation through an aberrant activation of multiple signaling pathways, such as Stat, Pi3K and Ras/Erk. The der9 encodes for the reciprocal ABL/BCR fusion proteins the p40ABL/BCR, present in 65% of patients with chronic myeloid leukemia (CML) and the p96ABL/BCR, detectable in 100% of patients with Ph+ acute lymphatic leukemia (ALL). ABL/BCRs are oncogenes able to influence the lineage commitment of hematopoietic progenitors. Aim of this study was to further disclose the role of p96ABL/BCR for the pathogenesis of Ph+ ALL. We co-expressed p96ABL/BCRand p185BCR/ ABL from a p2A peptide-linked multi-cistronic retroviral vector, which allows the expression of multiple proteins from a single open reading frame (ORF) to identical levels. The co- expression of p96ABL/BCR enhanced the kinase activity and, as a consequence, the transformation potential of p185BCR/ABL in factor dependent progenitor cells and untransformed fibroblasts. Targeting p96ABL/BCR by RNAi inhibited growth of Ph+ ALL cell lines and primary Ph+ ALL patient-derived long-term cultures (PD-LTCs). Furthermore p96ABL/BCR negatively influenced the response to AKI in these models as shown by an increased response to AKI when p96ABL/BCR was down-regulated. Our in vitro and in vivo stem cell studies on murine fetal liver cells and adult HSCs revealed a functional hierarchy between p96ABL/BCR and p185BCR/ABL. In fact, p96ABL/BCR strongly increased stem cell capacity in replating efficiency and colony forming unit-spleen day 12 (CFU-S12) assays, whereas p185BCR/ABL showed no effect. In contrast co-expression of p96ABL/BCR and p185BCR/ABL increased significantly both serial replating potential and CFU-S12 colony formation as compared to p96ABL/BCR alone. In a syngeneic mouse model co-expression of p96ABL/BCR abolished the capacity of p185BCR/ABL to induce a CML-like disease and led to the induction of ALL. Taken together our here presented data reveal an important role of p96ABL/BCR for the pathogenesis of Ph + ALL

The functional interplay between the t(9;22)-associated fusion proteins BCR/ABL and ABL/BCR in Philadelphia chromosome positive Acute Lymphatic Leukemia

The successful targeting of BCR/ABL by selective ABL-kinase inhibitors (AKI) such as Imatinib, Nilotinib, or Dasatinib alone is unable to eradicate the leukemic clone in Philadelphia chromosome positive (Ph+ ) leukemia. The t(9;22)(q34;q11) is a balanced translocation. Der22 involves the BCR (breakpoint cluster region) gene locus with two principal breaks: the M-bcr, encoding for the p210BCR/ABL and the m-bcr, encoding for the 185BCR/ABL fusion proteins, respectively. The constitutively activated BCR/ABL kinase is responsible for the leukemic transformation through an aberrant activation of multiple signaling pathways, such as Stat, Pi3K and Ras/Erk. The der9 encodes for the reciprocal ABL/BCR fusion proteins the p40ABL/BCR, present in 65% of patients with chronic myeloid leukemia (CML) and the p96ABL/BCR, detectable in 100% of patients with Ph+ acute lymphatic leukemia (ALL). ABL/BCRs are oncogenes able to influence the lineage commitment of hematopoietic progenitors. Aim of this study was to further disclose the role of p96ABL/BCR for the pathogenesis of Ph+ ALL. We co-expressed p96ABL/BCRand p185BCR/ ABL from a p2A peptide-linked multi-cistronic retroviral vector, which allows the expression of multiple proteins from a single open reading frame (ORF) to identical levels. The co- expression of p96ABL/BCR enhanced the kinase activity and, as a consequence, the transformation potential of p185BCR/ABL in factor dependent progenitor cells and untransformed fibroblasts. Targeting p96ABL/BCR by RNAi inhibited growth of Ph+ ALL cell lines and primary Ph+ ALL patient-derived long-term cultures (PD-LTCs). Furthermore p96ABL/BCR negatively influenced the response to AKI in these models as shown by an increased response to AKI when p96ABL/BCR was down-regulated. Our in vitro and in vivo stem cell studies on murine fetal liver cells and adult HSCs revealed a functional hierarchy between p96ABL/BCR and p185BCR/ABL. In fact, p96ABL/BCR strongly increased stem cell capacity in replating efficiency and colony forming unit-spleen day 12 (CFU-S12) assays, whereas p185BCR/ABL showed no effect. In contrast co-expression of p96ABL/BCR and p185BCR/ABL increased significantly both serial replating potential and CFU-S12 colony formation as compared to p96ABL/BCR alone. In a syngeneic mouse model co-expression of p96ABL/BCR abolished the capacity of p185BCR/ABL to induce a CML-like disease and led to the induction of ALL. Taken together our here presented data reveal an important role of p96ABL/BCR for the pathogenesis of Ph + ALL

BCR: a new target in resistance mediated by BCR/ABL-315I?

Targeting BCR/ABL with Tyrosine kinase inhibitors (TKIs) is a proven concept for the treatment of Philadelphia chromosome-positive (Ph+) leukemias. The most important mechanism of resistance against TKIs is the selection of leukemic clones driven by BCR/ABL harboring point mutations. The “gatekeeper”mutation T315I confers resistance against all approved TKIs, with the only exception of ponatinib, a multi-targeted kinase inhibitor. Besides resistance to TKIs, T315I also confers additional features to the leukemogenic potential of BCR/ABL, involving endogenous BCR. Therefore we studied the role of BCR for the effects of T315I on BCR/ABL mutants lacking functional domains indispensable for the oncogenic activity of BCR/ABL. As models we used the factor independent growth of murine myeloid progenitor 32D cells and the transformation of Rat-1 fibroblasts both mediated by BCR/ABL. Here we report that T315I restores the capacity to mediate factor-independent growth and transformation potential of loss-of-function mutants of BCR/ABL. Targeting endogenous Bcr abrogated the capacity of oligomerization deficient mutant of BCR/ ABL-T315I to mediate factor independent growth of 32D cells and strongly reduced their transformation potential in Rat-1 cells, as well as led to the up-regulation of mitogen activated protein kinase (MAPK) pathway. Our data show that the T315I restores the capacity of loss-of-function mutants to transform cells which is dependent on the transphosphorylation of endogenous Bcr, which becomes a putative therapeutic target to overcome resistance by T315I

BCR: a new target in resistance mediated by BCR/ABL-315I?

Targeting BCR/ABL with Tyrosine kinase inhibitors (TKIs) is a proven concept for the treatment of Philadelphia chromosome-positive (Ph+) leukemias. The most important mechanism of resistance against TKIs is the selection of leukemic clones driven by BCR/ABL harboring point mutations. The “gatekeeper”mutation T315I confers resistance against all approved TKIs, with the only exception of ponatinib, a multi-targeted kinase inhibitor. Besides resistance to TKIs, T315I also confers additional features to the leukemogenic potential of BCR/ABL, involving endogenous BCR. Therefore we studied the role of BCR for the effects of T315I on BCR/ABL mutants lacking functional domains indispensable for the oncogenic activity of BCR/ABL. As models we used the factor independent growth of murine myeloid progenitor 32D cells and the transformation of Rat-1 fibroblasts both mediated by BCR/ABL. Here we report that T315I restores the capacity to mediate factor-independent growth and transformation potential of loss-of-function mutants of BCR/ABL. Targeting endogenous Bcr abrogated the capacity of oligomerization deficient mutant of BCR/ ABL-T315I to mediate factor independent growth of 32D cells and strongly reduced their transformation potential in Rat-1 cells, as well as led to the up-regulation of mitogen activated protein kinase (MAPK) pathway. Our data show that the T315I restores the capacity of loss-of-function mutants to transform cells which is dependent on the transphosphorylation of endogenous Bcr, which becomes a putative therapeutic target to overcome resistance by T315I

The functional interplay between the t(9;22)-associated fusion proteins BCR/ABL and ABL/BCR in Philadelphia chromosome-positive Acute Lymphatic Leukemia

The hallmark of Philadelphia chromosome positive (Ph+) leukemia is the BCR/ABL kinase, which is successfully targeted by selective ATP competitors. However, inhibition of BCR/ABL alone is unable to eradicate Ph+ leukemia. The t(9;22) is a reciprocal translocation which encodes not only for the der22 (Philadelphia chromosome) related BCR/ABL, but also for der9 related ABL/BCR fusion proteins, which can be detected in 65% of patients with chronic myeloid leukemia (CML) and 100% of patients with Ph+ acute lymphatic leukemia (ALL). ABL/BCRs are oncogenes able to influence the lineage commitment of hematopoietic progenitors. Aim of this study was to further disclose the role of p96ABL/BCR for the pathogenesis of Ph+ ALL. The co-expression of p96ABL/BCR enhanced the kinase activity and as a consequence, the transformation potential of p185BCR/ABL. Targeting p96ABL/BCR by RNAi inhibited growth of Ph+ ALL cell lines and Ph+ ALL patient-derived long-term cultures (PD-LTCs). Our in vitro and in vivo stem cell studies further revealed a functional hierarchy of p96ABL/BCR and p185BCR/ABL in hematopoietic stem cells. Co-expression of p96ABL/BCR abolished the capacity of p185BCR/ABL to induce a CML-like disease and led to the induction of ALL. Taken together our here presented data reveal an important role of p96ABL/BCR for the pathogenesis of Ph+ ALL

Targeting p96^{<i>ABL/BCR</i>} in Ph⁺ ALL cells.

<p>(A) SupB15 and K562 cells were lentivirally transduced with shRNA against p96^{<i>ABL/BCR</i>} (siR961 and siR962) and a control shRNA (NTC). The expression of p96^{<i>ABL/BCR</i>} and/or BCR was detected by immunoblotting using anti-BCR antibody. Tubulin was used as loading control. Proliferation was measured using XTT-assay after 3 days. One representative experiment in triplicates ± SD of at least three yielding similar results is given; (B) The effect of targeting p96^{<i>ABL/BCR</i>} by shRNA in SupB15 on STAT5 and ERK1/2 pathway was detected using the indicated antibodies; (C) Down-regulation of p96^{<i>ABL/BCR</i>} in Ph⁺ ALL PD-LTCs by shRNA. Ph⁺ ALL PD-LTCs—PH: fully TKI-responsive; BV: TKI-resistant; as controls were used: HP (Ph^- ALL patient) and VG: t(12;9)-TEL/ABL-positive ALL. The effect of shRNAs on the expression of p96^{<i>ABL/BCR</i>} was tested by immunoblotting using the indicated antibodies and by q-RT-PCR for PH and BV. The Ct values were normalized to that of GAPDH and results are represented as 2^-ΔΔCt. Proliferation was measured by XTT-assay. The mean of at least experiments is given ± SD.</p